Molecular Genetics of Cutaneous Lupus Erythematosus

This article examines the evidence of a genetic basis for cutaneous forms of lupus erythematosus (LE), namely, subacute cutaneous LE (SCLE) and discoid LE (DLE).

The current theory is that multiple genes, including particular allelic polymor- phisms, may confer susceptibility to these LE-specific skin diseases (Sontheimer 1996) and that perhaps some of these alleles may be shared with polymorphous light eruption (PLE), a common condition that is clinically related to lupus (Nyberg et al.

1997).

Sequeira (Sequeira 1903) described two pairs of sisters (not twins) affected by cutaneous LE (CLE), raising the possibility that it might be a familial condition. Since then, several studies have reported the occurrence of CLE, particularly DLE, in monozygotic twins (Steagall et al. 1962, Wojnarowska 1983) and first-degree relatives of lupus probands (Beckett and Lewis 1959, Leonhardt 1957). Gallo and Forde (Gallo and Forde 1966) suggested that inheritance of a “dominant gene,” with or without common environmental factors, may explain the observation of DLE across three generations of one family. A mathematical analysis of the age and sex distribution of DLE incidence in the population was also used in the 1960s by Rowell to support a genetic basis for DLE (Burch and Rowell 1968).

More recently, Lawrence et al. (Lawrence et al. 1987) investigated first-degree rela- tives of 37 patients with DLE in a case-control study. They found a significantly increased prevalence of DLE (3.5%) in 255 first-degree relatives of DLE probands compared with 0.5% in 664 controls. Heritability analysis suggested a polygenic inheritance, with 44% heritability. Several recent genome-wide marker scans for sys- temic LE (SLE) have subsequently been performed in families with multiple affected individuals to identify regions of the genome that may be linked to the disease phe- notype (Gaffney et al. 1998, 2000, Gray-McGuire et al. 2000, Lindqvist et al. 2000, Moser et al. 1998, Nath et al. 2001, Shai et al. 1999). These scans confirm that suscep- tibility to lupus is likely to be determined by multiple genetic regions, with different susceptibility loci in different ethnic groups.

It has long been known that certain conditions predispose to CLE. For example, DLE has been described in patients and carriers of X-linked and autosomal-recessive chronic granulomatous disease (Arnett 1997, Yeaman et al. 1992) and is also associ- ated with non-X-linked hyper-immunoglobulin M syndrome (Wolpert et al. 1998).

We and others have found a higher prevalence of PLE in patients with both SCLE and DLE than in controls (Millard et al. 2001a, Nyberg et al. 1997), suggesting that they may share a common genetic background. The study of these conditions may help shed light on the genetic basis of LE in the future.

Molecular Genetics

of Cutaneous Lupus Erythematosus

Thomas P. Millard

15

Techniques to Examine Susceptibility Genes in Cutaneous Lupus Erythematosus

There are several major approaches to the study of genetic susceptibility in any given complex (multifactorial) disease, including twin pair analysis, association analysis, family linkage studies (including “genome scans”), and transmission disequilibrium testing. Twin pair analysis is probably the best approach to investigate the relative importance of genetic and environmental factors in disease susceptibility; however, the prevalence of CLE is too low for a formal concordance study even in a large popu- lation-based twin sample. Association studies (case-control) examine the relationship between the disease and a given candidate gene in the population. They assume that the candidate gene is involved in the pathogenesis of the disease and that a specified allelic variant (polymorphism) of this gene will be overrepresented in patients com- pared with unaffected controls. For example, this approach has been used to support a role for corneodesmosin in psoriasis (Enerback et al. 2000). This technique requires careful phenotype selection and is vulnerable to the problem of matching the ethnic background of cases and controls (“population stratification”). Another potential problem is that the association between a candidate gene polymorphism and disease may exist only because the polymorphism is a marker for the real disease-causing allele, either at the same gene locus or at a nearby gene, with the marker and the disease alleles being in “linkage disequilibrium” (Ralston 1998).

Family linkage analysis has the advantage that it does not require a candidate locus and also avoids the problem of population stratification. However, it requires a large set of several hundred molecular markers to type polymorphisms throughout the entire genome to identify regions that are linked within the family to the disease.

These genome-wide scans, used in human SLE, have identified high “logarithm of odds” (lod) scores for several regions, including Fc γRIIA at band 1q23, the major his- tocompatibility complex (MHC) at 6p21.3, and 1q31, which includes the genes encod- ing interleukin (IL) 10 and Ro60 (Moser et al. 1998, Gaffney et al. 1998, Shai et al.

1999). No genome-wide searches have so far been performed in CLE, although DLE families with multiple affected individuals are probably sufficiently common for such an analysis in the future.

Transmission disequilibrium testing (TDT) assumes that a heterozygous parent should transmit the disease-associated allele to an affected child more often than the 50% expected from standard Mendelian inheritance (Lewis 2000). TDT therefore tests family linkage in the presence of association, avoiding the problem of popula- tion stratification, and may be used to narrow candidate regions identified through genome-wide searches. We are currently using TDT to investigate susceptibility genes for SCLE and DLE.

Candidate Genes in Cutaneous Lupus Erythematosus

Selection of candidate genes for analysis in complex multifactorial traits such as CLE

draws on multiple sources of information. In the case of LE, these include family link-

age studies in human and animal models of lupus, immunohistochemical analysis of

skin samples, and studies of alleles identified as possible candidates in other (related)

autoimmune diseases. For example, at least 10 loci have been found to predispose to LE in New Zealand lupus-prone mice (Kono et al. 1994), in addition to the previously mentioned loci that are linked to human lupus. In the murine model, genetic suscep- tibility seems to confer different levels of pathogenesis, including separate loci for autoantibody production, specific organ destruction, and mortality. Only one locus, the MHC (H-2 in mice), is linked to all three levels of disease.

Immunohistochemical analysis may be used to localize the expression of specific proteins within the skin of patients with lupus, perhaps implying abnormal regula- tion of the underlying genes that encode these proteins. For example, increased kera- tinocyte expression of intercellular adhesion molecule-1 (ICAM-1) has been demon- strated in evolving ultraviolet (UV)-induced lesions of CLE and PLE, but not in healthy controls (Nyberg et al. 1999). Thus, ICAM-1, its ligand, and upstream regula- tors may be deemed possible candidates to study (Norris et al. 1992).

Association in other autoimmune disorders is reported for various loci encoding cytokines, cytokine receptors, antioxidant enzymes, and adhesion molecules in rheumatoid arthritis, dermatomyositis, and SLE. It is therefore possible that the poly- morphisms at these loci may be candidates for the related autoimmune CLE.

Finally, a candidate gene may be inferred from knowing the therapeutic action of drugs used to treat the disease. For example, thalidomide, which inhibits tumor necrosis factor (TNF)- α, is particularly effective for treating SCLE and DLE (Wallace 1997). This suggests that TNF (or possibly one of its common polymorphisms) may contribute to the pathogenesis of CLE.

The Major Histocompatibility Complex

From such studies, a variety of candidate gene loci have emerged that may prove important in the pathogenesis of CLE. The most important of these loci to date are found within the MHC. The human MHC (Fig. 15.1) is a diverse genetic region that plays a crucial role in control of the immune response and that has recently been sequenced by the MHC Sequencing Consortium (1999). The human MHC genes, clus- tered together in a segment of chromosome 6 (6p21.3), are organized into three regions (I, II, and III) and encode three major classes of proteins: class I human leukocyte antigens (HLAs) (including the classical antigens A, B, and Cw), HLA class II antigens (DP, DQ, and DR), and class III molecules, including complement compo- nents, TNF ( α and β), and heat shock proteins.

HLA Genes and Cutaneous Lupus Erythematosus

In several serologic studies of the class I and class II HLA regions in patients with

SCLE (mainly Caucasian), the HLA A1, B8, DR3, DQ2, DRw52, C4null ancestral hap-

lotype has been consistently identified as a susceptibility haplotype for SCLE, partic-

ularly in patients seropositive for anti-Ro/SSA (Bielsa et al. 1991, Herrero et al. 1988,

Johansson-Stephansson et al. 1989, Provost et al. 1988, Sontheimer et al. 1981, 1982,

Vazquez-Doval et al. 1992, Watson et al. 1991), confirmed by our recent analysis of

HLA genes in 36 patients with SCLE (Millard et al. 2001b). This ancestral haplotype

is associated with susceptibility to a variety of other autoimmune diseases, including

insulin-dependent diabetes mellitus, dermatitis herpetiformis, and myasthenia gravis

(Price et al. 1999).

Watson et al. (Provost and Watson 1993, Watson et al. 1991) found that this associ- ation was only present in SCLE, SLE, and Sjögren’s syndrome in the presence of anti- Ro/SSA, suggesting that the immunogenetic association is primarily with the produc- tion of antibody. There is substantial evidence to support the pathogenic role of the anti-Ro/SSA antibody in SCLE (Ben-Chetrit 1993), where circulating anti-Ro/SSA binds keratinocytes expressing surface Ro/SSA antigen, leading to the destruction of basal keratinocytes (Norris 1993) (Fig. 15.2). In addition to controlling the presence or absence of the anti-Ro/SSA response, the MHC may also determine the level of the response; Harley et al. (Harley et al. 1986) found that possession of both HLA DQ1 and DQ2 led to the highest titers of anti-Ro/SSA. This MHC specificity suggests that class II HLA antigens may determine whether the individual can present fragments of Ro/SSA antigen to their lymphocytes.

The Ro/SSA 60-kDa protein (Ro60 or SSA2) is the major component of the Ro ribonucleoprotein (RNP) complex [in stable association with a human cytoplasmic RNA (hY RNA) and the La/SSB protein, Fig. 15.3], to which an immune response is a specific feature of several autoimmune diseases, including SCLE and SLE. We recently characterized the Ro60 gene structure (Fig. 15.4) and examined whether any observed sequence alterations were associated with serum anti-Ro/SSA antibody in SCLE and could therefore be of pathogenic significance (Millard et al. 2002). Het- eroduplex analysis of polymerase chain reaction (PCR) products from patients and controls spanning all Ro60 exons (1 to 8) revealed a common bandshift in the PCR products spanning exon 7. Sequencing of the corresponding PCR products demon-

Fig. 15.1.

Abbreviated gene map of the human MHC at 6p21.3 illustrating the major loci to which the text refers. The illustrated class II loci are, themselves, composed of multi- ple genes that contribute to the class II antigen structure.

HSP, heat shock protein;

TNF, tumor necrosis factor

strated an A>G substitution at nucleotide position 1318-7, within the consensus acceptor splice site of exon 7 (GenBank XM001901). The allele frequencies were major allele A (0.71) and minor allele G (0.29) in 72 control chromosomes, with no significant differences among patients with SCLE (anti-Ro/SSA positive), patients with DLE (anti-Ro/SSA negative), and healthy controls, suggesting no relationship between this nucleotide substitution and generation of anti-Ro/SSA.

Fig. 15.3.

Organization of the Ro/SSA RNP complex (Gordon et al. 1994). hY RNA, human cytoplasmic RNA

Fig. 15.2.

Probable pathogenic mechanism of photosensitive skin lesions in LE. Ultraviolet radi-

ation (UVR) stimulates the cell surface expression of nuclear antigens, including Ro/SSA, on the

surface of keratinocytes and induces E-selectin and intercellular adhesion molecule-1 (ICAM-

1) expression on dermal endothelial cells, which leads to the margination and local migration of

lymphocytes. Norris (Norris 1993) proposed this model of photosensitive LE, whereby circulat-

ing anti-Ro/SSA antibody binds keratinocytes that express this surface Ro/SSA antigen, leading

to antibody-dependent cellular cytotoxicity by the infiltrating cytotoxic lymphocytes and the

subsequent destruction of basal keratinocytes. Casciola-Rosen and Rosen (Casciola-Rosen and

Rosen 1997) have added to this model by describing the expression of Ro/SSA antigen in “sur-

face blebs” of UVB-irradiated apoptotic keratinocytes, which may contribute to induction of

autoimmunity to Ro/SSA. IL-1, interleukin-1; TNF, tumor necrosis factor

A relatively small number of studies have examined HLA associations in Cau- casian patients with DLE. The major associations include the A1, B8, DR3 and also the B7, DR2 haplotypes (Fowler et al. 1985, Knop et al. 1990, Millard et al. 1977), although other studies have found no HLA associations with DLE (Bielsa et al. 1991, Tongio et al. 1982). Our own data indicate a significant association with the previously men- tioned haplotypes and DLE (Millard et al. 2001b). Finally, the photosensitive “butter- fly rash” of lupus (acute CLE) rarely occurs outside the context of active SLE, so little effort has been made to determine any specific HLA associations (Sontheimer and Provost 1997).

Complement Genes

The MHC also includes genes for various complement components (C2, C4A, C4B, and factor B) in the class III region (Meo et al. 1977), between class I and class II, which have been implicated in the pathogenesis of CLE. Inherited deficiencies of components C2 and C4 are associated with DLE (Braathen et al. 1986, Provost et al.

1983), SCLE (Callen et al. 1987, Levy et al. 1979, Provost et al. 1983), and the presence of anti-Ro/SSA (Meyer et al. 1985, Provost et al. 1983). In addition, lupus profundus has been reported in patients with partial deficiency of both C4 allotypes (Burrows et al. 1991, Nousari et al. 1999). The proposed basis for these associations includes either a failure to clear immune complexes and apoptotic cells or linkage disequi- librium with the real disease-predisposing locus (Levy et al. 1979, Sullivan 1998).

TNF Genes

TNF is encoded by a class III gene of the MHC (Carroll et al. 1987, MHC Sequencing Consortium 1999). TNF has been implicated in the pathogenesis of CLE following UVR (Kock 1990, Norris 1993) (Fig. 15.2) since it stimulates expression of the Ro anti- gen on the keratinocyte surface. The rare –308A polymorphic form of TNF (TNF2)

Fig. 15.4.

Structural organization of the Ro60 gene. The coding region of the gene contains 8

exons spanning more than 16 kB of genomic DNA and ranging in size from 114 to greater than

580 bp. Exons are depicted by the vertical black shaded areas, and the start of the 5' and 3'

untranslated regions are in white. The exons are numbered above; introns are represented by

horizontal lines

(Abraham et al. 1999) is associated with increased UVB-induced TNF production in keratinocytes (Silverberg et al. 1999) and has demonstrated a strong association with SCLE (Werth and Sullivan 1999). TNF –308A does, however, lie on the A1, B8, DR3 extended haplotype in Caucasians (Wilson et al. 1993) and may therefore demon- strate association only because of linkage disequilibrium. However, a recent analysis in patients with SLE suggests that both TNF –308A and HLA-DR3 contribute inde- pendently to lupus susceptibility (Rood et al. 2000).

Heat Shock Protein Genes

The three heat shock protein 70 (Hsp70) genes are located within the class III MHC region, and linkage disequilibrium with other HLA genes has led several authors to investigate the role of Hsp70 genes in susceptibility to autoimmune and allergic dis- ease (Aron et al. 1999). The activation of Hsp gene expression (the “stress response”) is a cellular mechanism that protects cells against stresses such as heat, UVR, cytokines, and chemicals (Muramatsu et al. 1992, Stephanou et al. 1997). Ghoreishi et al. (Ghoreishi et al. 1993) used immunohistologic analysis to demonstrate diffusely increased Hsp70 expression in the lesional skin of patients with SLE vs controls and DLE samples. Furukawa et al. (Furukawa et al. 1993) observed increased binding of anti-Ro/SSA antibodies to keratinocytes after incubation with a prostaglandin stres- sor that is known to induce Hsp formation, suggesting that heat shock proteins may be involved in the expression of Ro antigen at the cell surface. Various polymor- phisms exist for the Hsp70 genes (Bolla et al. 1998, Esaki et al. 1999), although none have yet been examined for association in CLE.

Candidate Loci Outside the MHC

Several genetic regions outside the MHC seem to confer susceptibility to cutaneous forms of LE or demonstrate association or linkage with the anti-Ro/SSA response, including loci encoding cytokines, cytokine receptors, molecules involved in antigen recognition, and antioxidant enzymes, all of which are plausible candidates and are summarized in Table 15.1.

IL-1 Gene Cluster

The primary cytokine IL-1 is a major proinflammatory cytokine, encoded by a gene cluster at band 2q13, comprising IL-1 α and IL-1β (synthesized by keratinocytes and Langerhans’ cells, respectively) and the IL-1 receptor antagonist gene (IL-1RN), which has been associated with photosensitivity in LE and with DLE by two separate teams in case-control studies (Blakemore et al. 1994, Suzuki et al. 1997). In our association analysis, we found that IL1B +3954 T was significantly less frequent in patients with SCLE (28%) compared with controls (47%; P=0.039), although this was lost on cor- rection for multiple testing (Millard et al. 2001c).

IL-10

Linkage in human lupus has been shown for band 1q31 (Moser et al. 1998), within

which lies the gene encoding IL-10 (Eskdale et al. 1997, Kim et al. 1992). IL-10 is

expressed by UVB-stimulated keratinocytes and is chemotactic for CD8

T cells.It pro-

motes an inflammatory response through its effects on B cells in lupus, whose produc-

tion of immunoglobulin is largely IL-10 dependent (Llorente et al.1995).It also up-reg- ulates the expression of ICAM-1 and E-selectin on human dermal endothelial cells (Palmetshofer et al. 1994). Three functional single nucleotide polymorphisms (SNPs) of the IL-10 gene promoter were reported by Turner et al. (Turner et al. 1997), includ- ing –1082 G/A, –819 C/T, and –592 C/A, who showed that they influenced in vitro pro- duction of IL-10 by mononuclear cells.Comparing the overall haplotype combinations at these three loci, significant distortion was demonstrated between anti-Ro/SSA-pos- itive and anti-Ro/SSA-negative SLE cases (P=0.005), with overrepresentation of the GCC and ACC haplotypes in the former group (Lazarus et al. 1997). This suggests that

Table 15.1.

Genes outside the MHC

that seem to confer susceptibility to cutaneous forms of lupus erythematosus (LE) or demonstrate association or linkage with the anti-Ro/SSA response

Gene Locus Evidence

1. Cytokine genes

Interleukin-1 gene 2q13 Association of an IL-1 RA

cluster (IL-1A, B, and RA) allele with DLE and with

photosensitivity in SLE.

Interleukin-10 (IL-10) 1q31 Linkage of 1q31 to human LE.

Association of three IL-10 SNPs with anti-Ro produc- tion in SLE.

2. Adhesion molecule/

receptor genes

Intercellular adhesion 19p13.3-p13.2 Increased keratinocyte

molecule-1 (ICAM1) expression of ICAM-1 in

CLE.

E-selectin (SELE) 1q23–25 Up-regulated endothelial

expression in the skin of patients with cutaneous LE vs controls.

Fc gamma receptor II 1q23 Linkage of 1q23 to human

(FCGR2A) systemic LE. Necessary for

ADCC (Fig. 15.4).

T-cell receptor (TCR) 7q35 Association of two RFLPs, for

C β1 and Cβ2 TCRs Cb1 and Cb2, with anti-

Ro/SSA production in SLE.

3. Antioxidant enzyme genes

Glutathione S-trans- 1p13 Association of GSTM1 null

ferase M1 (GSTM1) status and anti-Ro/SSA pro-

duction in SLE.

4. Apoptosis genes

Fas (TNFRSF6) 10q24.1 Association of an SNP with

photosensitivity in SLE

a

Genes within the MHC are illustrated in Fig. 15.1.

ADCC, antibody-dependent cellular cytotoxicity; CLE, cutaneous lupus erythematosus; DLE,

discoid LE; MHC, major histocompatibility complex; RA, receptor antagonist; RFLP, restriction

fragment length polymorphism; SLE, systemic LE; SNP, single nucleotide polymorphism.

IL-10 may be important in generation of the immune response to Ro and, therefore, potentially relevant to SCLE,although our initial study found no association with SCLE or DLE for either the –819 or –1082 SNPs (Millard et al. 2001c).

T-Cell Receptor C

Gene

Genes encoding the T-cell receptor (TCR) have demonstrated an association with the generation of anti-Ro/SSA. Frank et al. (Frank et al. 1990) reported an association between a set of restriction fragment length polymorphisms (RFLPs) for TCRs C

1 and C

2 (Bgl II 9.8-kb and Kpn I 1.75-kb) that was present in 76% of patients with SLE and anti-Ro/SSA but in only 41% of patients with SLE without anti-Ro/SSA (P=0.002). The same group found that certain HLA DQ types, in combination with the TCR C

RFLPs, increased the strength of this association (Scofield et al. 1994).

This molecular specificity was cited as evidence that the breaking of tolerance to the Ro proteins in lupus requires the association of a class II HLA molecule with a frag- ment of Ro peptide and a particular TCR form.

Glutathione S-Transferase

The antioxidant enzymes encoded by the glutathione S-transferase (GST) genes are widely expressed in mammalian tissues. Ollier et al. (Ollier et al. 1996) examined the role of the GSTM1 null polymorphisms in the production of anti-Ro/SSA and anti- La/SSB in SLE using PCR to identify GSTM1 [chromosome band 1p13 (Pearson et al.

1993)] null homozygotes. A significant association was demonstrated between the Ro

/La

phenotype in SLE and GSTM1 null status, implicating oxidant stress in the loss of immunologic tolerance to Ro/SSA antigen.

Adhesion Molecules

ICAM-1 and E-selectin are potential candidate genes for CLE. ICAM-1 is usually expressed at very low levels on keratinocytes, but increased keratinocyte expression has been demonstrated in evolving lesions of CLE and PLE (Nyberg et al. 1999, Nor- ris et al. 1992). Two functional polymorphisms of the ICAM-1 gene (ICAM1) were reported by Vora et al. (Vora et al. 1994), including G/R at codon 241 and K/E at codon 469, which therefore represent plausible candidates for CLE. The endothelial adhe- sion molecule E-selectin is also up-regulated in the skin of patients with CLE and patients with PLE compared with controls (Nyberg et al. 1999); elevated serum levels of soluble E-selectin have also been described in patients with DLE (Nyberg and Stephansson 1999). The E-selectin gene at band 1q23–25 (Collins et al. 1991) contains an A/C SNP at position 561, coding for serine or arginine at codon 128 (Wenzel et al.

1994a), which, so far, has demonstrated clinical association with atheromatous vascu- lar disease (Wenzel et al. 1994b).

Fc γ Receptor II

The Fc γ receptor II genes, at chromosome band 1q23 (Qiu et al. 1990), lie within an

area that has demonstrated strong linkage to SLE in humans, with an lod score of 3.37

(Moser et al. 1998). The Fc receptor is required by cytotoxic cells to initiate antibody-

dependent cellular cytotoxicity of keratinocytes, which is up-regulated in CLE

(Furukawa et al. 1999), and possibly directed against the Ro/SSA antigen (Norris

1993). The Fc γRIIa gene (FCGR2A) possesses an SNP (G/A) coding for arginine or

histidine at codon 131 (R/H131) in the EC2 domain of Fc γRIIa, which alters the abil- ity of the receptor to bind immunoglobulin G (Clark et al. 1989, Warmerdam et al.

1990).

Apoptosis Genes and Photosensitivity in Lupus

Apoptosis is a form of programmed cell death, over 6–48 h, that is characterized by cell shrinkage and nuclear condensation in response to the activation of the enzyme caspase 3 (Elkon 1997, Salmon and Gordon 1999). On early apoptotic keratinocytes, Casciola-Rosen (1997) reported the formation of surface blebs, which are highly enriched with several lupus autoantigens, including Ro/SSA; in genetically suscepti- ble individuals, expression of this autoantigen is proposed to initiate an autoantibody response. Multiple stimuli, including UVR, cytokines, cytotoxic T cells, and cytotoxic drugs, are capable of inducing apoptosis (Arnold et al. 1999, Danno and Horio 1982, Elkon 1997, Haake and Polakowska 1993, Stone et al. 1998). The Fas transmembrane glycoprotein receptor (Fas, encoded by TNFRSF6) has an intracellular death domain that initiates a cascade of events when Fas binds external Fas ligand, leading to death of the cell by apoptosis. In normal human skin, Fas is found mainly in the basal layer of the epidermis; expression then gradually diminishes toward the stratum granulo- sum. The specific role of Fas and Fas ligand in human CLE is still a matter of debate, but both molecules are expressed on infiltrating cells around blood vessels and hair follicles (Fushimi et al. 1998, Nakajima et al. 1997). Consistent with this co-expression of Fas and Fas ligand around hair follicles, apoptotic cells in this region were found (Nakajima et al. 1997).

In murine models, the Fas/Fas ligand axis may be involved in LE. Mice that are homozygous for the lpr (lymphoproliferation) recessive mutation accumulate large numbers of CD3

CD4

CD8

T cells, which lead to the induction or acceleration of sys- temic autoimmunity (Kono and Theofilopoulos 1997, Takahashi et al. 1994). The lpr mutation on mouse chromosome 19 causes a point mutation in Fas that abolishes its ability to transduce the apoptotic signal.A recent study of MRL/n (control) mice found that they develop LE-like skin lesions later in life than the closely related MRL/lpr (homozygous) mice (Furukawa et al. 1996). In humans, the Fas gene is located on chro- mosome band 10q24.1 (Inazawa et al. 1992). Huang et al. (Huang et al. 1999) examined a Fas polymorphism, the MvaI RFLP (MvaI*1/ MvaI*2, caused by an A/G SNP at the -670 nucleotide position) in 103 Caucasian patients with SLE and found that MvaI*2 homozygosity was significantly higher in patients with photosensitive SLE, but poly- morphic Fas loci have not yet been examined by association or linkage in CLE.

Summary

The genetic architecture of LE is far from understood. The most significant immuno-

genetic associations to date have been found in the presence of anti-Ro/SSA and/or

anti-La/SSB in CLE and SLE, where HLA, TNF, complement, IL-10, TCR, and GST

genes may be involved. However, other LE-specific associations, outside the context of

anti-Ro/SSA, have been less well characterized to date. For CLE, where the phenotype

can be accurately characterized, there are still numerous candidate gene loci in the wings.

Acknowledgements. This article is adapted (with written permission from Blackwell Science) from a review article of the same title (Millard and McGregor 2001d).

References

Abraham LJ, Kroeger KM (1999) Impact of the –308 TNF promoter polymorphism on the tran- scriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol 66:562–566 Arnett FC (1997) The Genetics of human lupus. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus

erythematosus. Williams & Wilkins, Baltimore, pp 77–117

Arnold R, Seifert M, Asadullah K, Volk HD (1999) Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: modulation by cytokines. J Immunol 162:

7140–7147

Aron Y, Busson M, Polla BS, Dusser D, Lockhart A, Swierczewski E, Favatier F (1999) Analysis of hsp70 gene polymorphism in allergic asthma. Allergy 54:165–170

Beckett AG, Lewis JG (1959) Familial lupus erythematosus: a report of two cases. Br J Dermatol 71:360–363

Ben-Chetrit E (1993) The molecular basis of the SSA/Ro antigens and the clinical significance of their autoantibodies. Br J Rheumatol 32:396–402

Bielsa I, Herrero C, Ercilla G, Collado A, Font J, Ingelmo M, Mascaro JM (1991) Immunogenetic findings in cutaneous lupus erythematosus. J Am Acad Dermatol 25:251–257

Blakemore AI, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW (1994) Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus.

Arthritis Rheum 37:1380–1385

Bolla MK, Miller GJ, Yellon DM, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F, Latchman DS, Humphries SE, Day IN (1998) Analysis of the association of a heat shock protein 70–1 gene promoter polymorphism with myocardial infarction and coronary risk traits. Dis Markers 13:227–235

Braathen LR, Bratlie A, Teisberg P (1986) HLA genotypes in a family with a case of homozygous C2 deficiency and discoid lupus erythematosus. Acta Derm Venereol 66:419–422

Burch PR, Rowell NR (1968) The sex- and age-distributions of chronic discoid lupus ery- thematosus in four countries. Possible aetiological and pathogenetic significance. Acta Derm Venereol 48:33–46

Burrows NP, Walport MJ, Hammond AH, Davey N, Jones RR (1991) Lupus erythematosus pro- fundus with partial C4 deficiency responding to thalidomide. Br J Dermatol 1991 125:62–67 Callen JP, Hodge SJ, Kulick K, Stelzer G, Buchino JJ (1987) Subacute cutaneous lupus erythe-

matosus in multiple members of a family with C2 deficiency. Arch Dermatol 123:66–70 Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T

(1987) Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci USA 84:8535–8539

Casciola-Rosen L, Rosen A (1997) Ultraviolet light-induced keratinocyte apoptosis: a potential mechanism for the induction of skin lesions and autoantibody production in LE. Lupus 6:175–180

Clark MR, Clarkson SB, Ory PA, Stolman N, Goldstein JM (1989) Molecular basis for a polymor- phism involving Fc receptor II on human monocytes. J Immunol 143:1731–1734

Collins T, Williams A, Johnston GI, Kim J, Eddy R, Shows T, Giml MA Jr, Bevilacqua MP (1991) Structure and chromosomal location of the gene for endothelial-leukocyte adhesion mole- cule 1. J Biol Chem 266:2466–2473

Danno K, Horio T (1982) Formation of UV-induced apoptosis relates to the cell cycle. Br J Der-

matol 107:423–428

Elkon KB (1997) Apoptosis. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus.

Williams & Wilkins, Baltimore, pp 133–142

Enerback C, Enlund F, Inerot A, Samuelsson L, Wahlstrom J, Martinsson T (2000) S gene (Cor- neodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA- linked S gene. J Invest Dermatol 114:1158–1163

Esaki M, Furuse M, Matsumoto T, Aoyagi K, Jo Y, Yamagata H, Nakano H, Fujima M (1999) Poly- morphism of heat-shock protein gene HSP70-2 in Crohn disease: possible genetic marker for two forms of Crohn disease. Scand J Gastroenterol 34:703–707

Eskdale J, Kube D, Tesch H, Gallagher G (1997) Mapping of the human IL10 gene and further characterization of the 5’ flanking sequence. Immunogenetics 46:120–128

Fowler JF, Callen JP, Stelzer GT, Cotter PK (1985) Human histocompatibility antigen associations in patients with chronic cutaneous lupus erythematosus. J Am Acad Dermatol 12:73–77 Frank MB, McArthur R, Harley JB, Fujisaku A (1990) Anti-Ro(SSA) autoantibodies are associated

with T cell receptor beta genes in systemic lupus erythematosus patients. J Clin Invest 85:33–39 Furukawa F, Ikai K, Matsuyoshi N, Shimizu K, Imamura S (1993) Relationship between heat shock protein induction and the binding of antibodies to the extractable nuclear antigens on cultured human keratinocytes. J Invest Dermatol 101:191–195

Furukawa F, Kanauchi H, Wakita H, Tokura Y, Tachibana T, Horiguchi Y, Imamura S, Ozaki S, Takigawa M (1996) Spontaneous autoimmune skin lesions of MRL/n mice: autoimmune dis- ease-prone genetic background in relation to Fas-defect MRL/1pr mice. J Invest Dermatol 107:95–100

Furukawa F, Itoh T, Wakita H, Yagi H, Tokura Y, Norris DA, Takigawa M (1999) Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity. Clin Exp Immunol 118:164–170

Fushimi M, Furukawa F, Tokura Y, Itoh T, Shirahama S, Wakita H, Takigawa M (1998) Membra- nous and soluble forms of Fas antigen in cutaneous lupus erythematosus. J Dermatol 25:302–308

Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ock- endenTC, Messner RP, King RA, Rich SS, Behrens TW (1998) A genome-wide search for sus- ceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 95:14875–14879

Gaffney PM, Ortmann WA, Selby, Shark KB, Ockenden TC, Rohlf KE, Walgrave NL, Boyum WP, Malmgren ML, Miller ME, Kearns GM, Mesner RP, King RA, Rich SS, Behrens TW (2000) Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am J Hum Genet 66:547–556 Gallo RC, Forde DL (1966) Familial chronic discoid lupus erythematosus and hypergammaglob-

ulinemia. Arch Intern Med 117:627–631

Ghoreishi M, Katayama I, Yokozeki H, Nishioka K (1993) Analysis of 70 KD heat shock protein (HSP70) expression in the lesional skin of lupus erythematosus (LE) and LE related diseases.

J Dermatol 20:400–405

Gordon T, Topfer F, Keech C, Reynolds P, Chen W, Rischmueller M, McCluskey J (1994) How does autoimmunity to La and Ro initiate and spread? Autoimmunity 18:87–92

Gray-McGuire C, Moser KL, Gaffney PM, Kelly J,Yu H, Olson JM, Jedrey CM, Jacobs KB, Kimberly RP, Neas BR, Rich SS, Behrens TW, Harley JB (2000) Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16–15.2. Am J Hum Genet 67:1460–1469

Haake AR, Polakowska RR (1993) Cell death by apoptosis in epidermal biology. J Invest Derma- tol 101:107–112

Harley JB, Reichlin M, Arnett FC, Alexander EL, Bias WB, Provost TT (1986) Gene interaction at HLA-DQ enhances autoantibody production in primary Sjogren’s syndrome. Science 232:1145–1147

Herrero C, Bielsa I, Font J, Lozano F, Ercilla G, Lecha M, Ingelmo M, Mascaro JM (1988) Subacute

cutaneous lupus erythematosus: clinicopathologic findings in thirteen cases. J Am Acad Der-

matol 19:1057–1062

Huang QR, Danis V, Lassere M, Edmonds J, Manolios N (1999) Evaluation of a new Apo-1/Fas promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus patients. Rheumatol (Oxford) 38:645–651

Inazawa J, Itoh N, Abe T, Nagata S (1992) Assignment of the human Fas antigen gene (Fas) to 10q24.1. Genomics 14:821–822

Johansson-Stephansson E, Koskimies S, Partanen J, Kariniemi AL (1989) Subacute cutaneous lupus erythematosus. Genetic markers and clinical and immunological findings in patients.

Arch Dermatol 125:791–796

Kim JM, Brannan CI, Copeland NG, Jenkins NA, Khan TA, Moore KW (1992) Structure of the mouse IL-10 gene and chromosomal localization of the mouse and human genes. J Immunol 148:3618–3623

Knop J, Bonsmann G, Kind P, Doxiadis I, Vogeler U, Doxiadis G, Goerz G, Grosse-Wilde H (1990) Antigens of the major histocompatibility complex in patients with chronic discoid lupus ery- thematosus. Br J Dermatol 122:723–728

Kock A, Schwarz T, Kirnbauer R, Urbanski A, Perry P, Ansel JC (1990) Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 172:1609–1614

Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D, Theofilopoulos AN (1994) Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 91:

10168–10172

Kono DH, Theofilopoulos AN (1997) The Genetics of Murine Systemic Lupus Erythematosus. In:

Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus. Williams & Wilkins, Baltimore, pp 119–132

Lawrence JS, Martins CL, Drake GL (1987) A family survey of lupus erythematosus. 1. Heritabil- ity. J Rheumatol 14:913–921

Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV (1997) Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 24:2314–2317

Leonhardt T (1957) Familial hypergammaglobulinaemia and systemic lupus erythematosus.

Lancet 2:1200–1203

Levy SB, Pinnell SR, Meadows L, Snyderman R, Ward FE (1979) Hereditary C2 deficiency asso- ciated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies. Arch Dermatol 115:57–61

Lewis CM (2000) Using sib-pairs and parent-child trios in association studies. In: Spector TD, Snieder H, MacGregor AJ (eds) Advances in twin and sib-pair analysis. Greenwich Medical Media, London, pp 167–179

Lindqvist AK, Steinsson K, Johaneson B, Kristjansdottir H, Arnasson A, Grondal G, Jonasson I, Magnusson V, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME (2000) A susceptibility locus for human systemic lupus erythe- matosus (hSLE1) on chromosome 2q. J Autoimmun 14:169–178

Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Morel-Fourrier B, Brouet JC, Alarcon-Segovia D, Galanaud P, Emilie D (1995) Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythe- matosus. J Exp Med 181:839–844

Meo T, Atkinson JP, Bernoco M, Bernoco D, Ceppellini R (1977) Structural heterogeneity of C2 Complement protein and its genetic variants in man: a new polymorphism of the HLA region. Proc Natl Acad Sci USA 74:1672–1675

Meyer O, Hauptmann G, Tappeiner G, Ochs HD, Mascart-Lemone F (1985) Genetic deficiency of C4, C2 or C1q and lupus syndromes. Association with anti-Ro (SS-A) antibodies. Clin Exp Immunol 1985 62:678–684

MHC Sequencing Consortium (1999) Complete sequence and gene map of a human major his- tocompatibility complex. Nature 401:921–923

Millard LG, Rowell NR, Rajah SM (1977) Histocompatibility antigens in discoid and systemic

lupus erythematosus. Br J Dermatol 96:139–144

Millard TP, Lewis CM, Khamashta MA, Hughes GR, Hawk JL, McGregor JM (2001a) Familial clustering of polymorphic light eruption in relatives of lupus patients – evidence of a shared pathogenesis. Br J Dermatol 144:334–338

Millard TP, Kondeatis E, Vaughan RW, Lewis CM, Khamashta MA, Hughes GR, Hawk JL, McGregor JM (2001b) Polymorphic light eruption and the HLA DRB1*0301 extended haplotype are independent risk factors for cutaneous lupus erythematosus. Lupus 10:

473–479

Millard TP, Kondeatis E, Cox A, Wilson AG, Grabczynska SA, Carey BS, Lewis CM, Khamashta MA, Duff GM, Hughes GR, Hawk JL, Vaughan RW, McGregor JM (2001c) A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, poly- morphic light eruption and actinic prurigo. Br J Dermatol 145:229–236

Millard TP, McGregor JM (2001d) Molecular genetics of cutaneous lupus erythematosus. Clin Exp Dermatol 26:184–191

Millard TP, Ashton GHS, Kondeatis E, Vaughan RW, Hughes GR, Khamashta MA, Hawk JL, McGrath JA (2002) Human Ro60 genomic organization and sequence alterations in cuta- neous lupus erythematosus. Br J Dermatol 146:210–215

Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Hen- shall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB (1998) Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedi- grees. Proc Natl Acad Sci USA 95:14869–14874

Muramatsu T, Tada H, Kobayashi N, Yamji M, Shirai T, Ohnishi T (1992) Induction of the 72-kD heat shock protein in organ-cultured normal human skin. J Invest Dermatol 98:786–790 Nakajima M, Nakajima A, Kayagaki N, Honda M, Yagita H, Okumura K (1997) Expression of

Fas ligand and its receptor in cutaneous lupus: implication in tissue injury. Clin Immunol Immunopathol 1997 83:223–229

Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, Aston CE, Harley JB (2001) Evi- dence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo- related systemic lupus erythematosus. Am J Hum Genet 69:1401–1406

Norris DA (1993) Pathomechanisms of photosensitive lupus erythematosus. J Invest Dermatol 100:58S–68S

Norris PG, Barker JN, Allen MH, Leiferman KM, MacDonald DM, Haskard DO, Hawk JL (1992) Adhesion molecule expression in polymorphic light eruption. J Invest Dermatol 99:504–508 Nousari HC, Kimyai-Asadi A, Provost TT (1999) Generalized lupus erythematosus profundus in

a patient with genetic partial deficiency of C4. J Am Acad Dermatol 41:362–364

Nyberg F, Hasan T, Puska P, Stephansson E, Hakkinen M, Ranki A, Ros AM (1997) Occurrence of polymorphous light eruption in lupus erythematosus. Br J Dermatol 136:217–221

Nyberg F, Hasan T, Skoglund C, Stephansson E (1999) Early events in ultraviolet light-induced skin lesions in lupus erythematosus: expression patterns of adhesion molecules ICAM-1, VCAM-1 and E-selectin. Acta Derm Venereol 79:431–436

Nyberg F, Stephansson E (1999) Elevated soluble E-selectin in cutaneous lupus erythematosus.

Adv Exp Med Biol 455:153–159

Ollier W, Davies E, Snowden N, Alldersea J, Fryer A, Jones P, Strange R (1996) Association of homozygosity for glutathione-S-transferase GSTM1 null alleles with the Ro

/La

autoanti- body profile in patients with systemic lupus erythematosus. Arthritis Rheum 39:1763–1764 Palmetshofer A, Schwarz K, Mahnke R, Bhardway R, Luger TA, Schwarz T (1994) Interleukin-10

affects the expression of adhesion molecules on human dermal microvascular endothelial cells. Exp Dermatol 3:138 (Abstract)

Pearson WR, Vorachek WR, Xu SJ, Berger R, Hart I, Vannais D, Patterson D (1993) Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13. Am J Hum Genet 53:220–233

Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F (1999)

The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with mul-

tiple immunopathological diseases. Immunol Rev 167:257–274

Provost TT, Arnett FC, Reichlin M (1983) Homozygous C2 deficiency, lupus erythematosus, and anti-Ro (SSA) antibodies. Arthritis Rheum 26:1279–1282

Provost TT, Talal N, Bias W, Harley JB, Reichlin M, Alexander EL (1988) Ro(SS-A) positive Sjo- gren’s/lupus erythematosus (SC/LE) overlap patients are associated with the HLA-DR3 and/or DRw6 phenotypes. J Invest Dermatol 91:369–371

Provost TT, Watson R (1993) Anti-Ro(SS-A) HLA-DR3-positive women: the interrelationship between some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients.

J Invest Dermatol 100:14S-20S

Qiu WQ, de Bruin D, Brownstein BH, Pearse R, Ravetch JV (1990) Organization of the human and mouse low-affinity Fc gamma R genes: duplication and recombination. Science 248:732–735 Ralston SH (1998) Do genetic markers aid in risk assessment? Osteoporos Int 8 (Suppl

1):S37–S42

Rood MJ, van Krugten MV, Zanelli E, van der Linden MW, Keijsers V, Schreuder GM, Verduyn W, Westendorp RG, de Vries RR, Breedveld FC, Verweij CL, Huizinga TW (2000) TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythemato- sus. Arthritis Rheum 43:129–134

Salmon M, Gordon C (1999) The role of apoptosis in systemic lupus erythematosus. Rheumatol (Oxford) 38:1177–1183

Scofield RH, Frank MB, Neas BR, Horowitz RM, Hardgrave KL, Fujisaku A, McArthur R, Harley JB (1994) Cooperative association of T cell beta receptor and HLA-DQ alleles in the produc- tion of anti-Ro in systemic lupus erythematosus. Clin Immunol Immunopathol 72:335–341 Sequira JH (1903) Lupus erythematosus in two sisters. Br J Dermatol 15:171

Shai R, Quismorio FP, Li L, Kwon OJ, Morrison J, Wallace DJ, Neuwelt CM, Brautbar C, Gauder- man WJ, Jacob CO (1999) Genome-wide screen for systemic lupus erythematosus suscepti- bility genes in multiplex families. Hum Mol Genet 8:639–644

Silverberg NB, Liotta M, Paller AS, Pachman LM (1999) TNF-alpha –308 polymorphism (AA, GA) is associated with increased UVB induced keratinocyte TNF-alpha production in vitro.

Arthritis Rheum 42:S93(Abstract)

Sontheimer RD, Stastny P, Gilliam JN (1981) Human histocompatibility antigen associations in subacute cutaneous lupus erythematosus. J Clin Invest 67:312–316

Sontheimer RD, Maddison PJ, Reichlin M, Jordon RE, Stastny P, Gilliam JN (1982) Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus ery- thematosus. Ann Intern Med 97:664–671

Sontheimer RD (1996) Photoimmunology of lupus erythematosus and dermatomyositis: a spec- ulative review. Photochem Photobiol 63:583–594

Sontheimer RD, Provost TT (1997) Cutaneous manifestations of lupus erythematosus. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythemtosus. Williams & Wilkins, Baltimore, pp 569–623 Steagall RW, Ash HT, Fentanes LB (1962) Familial lupus erythematosus. Arch Dermatol 1962

85:394–396

Stephanou A, Amin V, Isenberg DA, Akira S, Kishimoto T, Latchman DS (1997) Interleukin 6 acti- vates heat-shock protein 90 beta gene expression. Biochem J 321:103–106

Stone MS, Robson KJ, LeBoit PE (1998) Subacute radiation dermatitis from fluoroscopy during coronary artery stenting: evidence for cytotoxic lymphocyte mediated apoptosis. J Am Acad Dermatol 38:333–336

Sullivan KE (1998) Complement deficiency and autoimmunity. Curr Opin Ped 10:600–606 Suzuki H, Matsui Y, Kashiwagi H (1997) Interleukin-1 receptor antagonist gene polymorphism

in Japanese patients with systemic lupus erythematosus. Arthritis Rheum 40:389–390 Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S (1994) Gener-

alized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969–976

Tongio MM, Fersing J, Hauptmann G, Mayer S, Grange D, Samsoen M, Groshans E (1982) HLA antigens in discoid lupus erythematosus. Acta Derm Venereol 62:155–157

Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinsin IV (1997) An investi-

gation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

Vazquez-Doval J, Ruiz E, Sanchez-Ibarrola A, Contreras F, Soto de Delas J, Quintanilla E (1992) Subacute cutaneous lupus erythematosus–clinical, histopathological and immunophenotyp- ical study of five cases. J Investig Allergol Clin Immunol 2:27–32

Vora DK, Rosenbloom CL, Beaudet AL, Cottingham RW (1994) Polymorphisms and linkage analysis for ICAM-1 and the selectin gene cluster. Genomics 21:473–477

Wallace DJ (1997) Occasional, innovative and experimental therapies. In: Wallace DJ and Hahn BH (eds) Dubois’ lupus erythemtosus. Williams & Wilkins, Baltimore, pp 1191–1202 Warmerdam PA, van de Winkel JG, Gosselin EJ, Capel PJ (1990) Molecular basis for a polymor-

phism of human Fc gamma receptor II (CD32). J Exp Med 172:19–25

Watson RM, Talwar P, Alexander E, Bias WB, Provost TT (1991) Subacute cutaneous lupus ery- thematosus-immunogenetic associations. J Autoimmun 4:73–85

Wenzel K, Hanke R, Speer A (1994a) Polymorphism in the human E-selectin gene detected by PCR-SSCP. Hum Gen 94:452–453

Wenzel K, Felix S, Kleber FX, Brachold R, Menke T, Schattke S, Schulte KL, Glaser C, Rohde K, Baumann G, Speer A (1994b) E-selectin polymorphism and atherosclerosis: an association study. Hum Mol Genet 3:1935–1937

Werth VP, Sullivan KE (1999) Strong association of a promoter polymorphism of tumour necro- sis factor-alpha (TNF-alpha) with a photosensitive form of cutaneous lupus erythematosus.

Arthritis Rheum 42:S105 (Abstract)

Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW (1993) An allelic poly- morphism within the human tumor necrosis factor alpha promoter region is strongly asso- ciated with HLA A1, B8, and DR3 alleles. J Exp Med 177:557–560

Wojnarowska F (1983) Simultaneous occurrence in identical twins of discoid lupus erythemato- sus and polymorphic light eruption. J R Soc Med 76:791–792

Wolpert KA, Webster AD, Whittaker SJ (1998) Discoid lupus erythematosus associated with a primary immunodeficiency syndrome showing features of non-X-linked hyper-IgM syn- drome. Br J Dermatol 138:1053–1057

Yeaman GR, Froebel K, Galea G, Ormerod A, Urbaniak SJ (1992) Discoid lupus erythematosus in

an X-linked cytochrome-positive carrier of chronic granulomatous disease. Br J Dermatol

126:60–65